High-Sensitivity Cardiac Troponin on Presentation to Rule Out Myocardial Infarction: A Stepped-Wedge Cluster Randomized Controlled Trial

Abstract

Background: High-sensitivity cardiac troponin assays enable myocardial infarction to be ruled out earlier, but the safety and efficacy of this approach is uncertain. We investigated whether an early rule-out pathway is safe and effective for patients with suspected acute coronary syndrome.

Methods: We performed a stepped-wedge cluster randomized controlled trial in the emergency departments of 7 acute care hospitals in Scotland. Consecutive patients presenting with suspected acute coronary syndrome between December 2014 and December 2016 were included. Sites were randomized to implement an early rule-out pathway where myocardial infarction was excluded if high-sensitivity cardiac troponin I concentrations were <5 ng/L at presentation. During a previous validation phase, myocardial infarction was ruled out when troponin concentrations were <99th percentile at 6 to 12 hours after symptom onset. The coprimary outcome was length of stay (efficacy) and myocardial infarction or cardiac death after discharge at 30 days (safety). Patients were followed for 1 year to evaluate safety and other secondary outcomes.

Results: We enrolled 31 492 patients (59±17 years of age [mean±SD]; 45% women) with troponin concentrations <99th percentile at presentation. Length of stay was reduced from 10.1±4.1 to 6.8±3.9 hours (adjusted geometric mean ratio, 0.78 [95% CI, 0.73-0.83]; P<0.001) after implementation and the proportion of patients discharged increased from 50% to 71% (adjusted odds ratio, 1.59 [95% CI, 1.45-1.75]). Noninferiority was not demonstrated for the 30-day safety outcome (upper limit of 1-sided 95% CI for adjusted risk difference, 0.70% [noninferiority margin 0.50%]; P=0.068), but the observed differences favored the early rule-out pathway (0.4% [57/14 700] versus 0.3% [56/16 792]). At 1 year, the safety outcome occurred in 2.7% (396/14 700) and 1.8% (307/16 792) of patients before and after implementation (adjusted odds ratio, 1.02 [95% CI, 0.74-1.40]; P=0.894), and there were no differences in hospital reattendance or all-cause mortality.

Conclusions: Implementation of an early rule-out pathway for myocardial infarction reduced length of stay and hospital admission. Although noninferiority for the safety outcome was not demonstrated at 30 days, there was no increase in cardiac events at 1 year. Adoption of this pathway would have major benefits for patients and health care providers. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03005158.

Keywords: biomarkers; chest pain; myocardial infarction; randomized controlled trial; troponin.

Figure 1.

Schematic diagram of the HiSTORIC trial design and the early rule-out pathway. A, A high-sensitivity cardiac troponin I assay with sex-specific 99th percentile thresholds was used to guide care and rule in myocardial infarction during all phases of the trial. During a validation phase of at least 6 months, cardiac troponin testing was performed at presentation and was repeated 6 or 12 hours after the onset of symptoms if indicated. Myocardial infarction was ruled out when high-sensitivity cardiac troponin concentrations were <99th percentile at presentation if symptom onset was >6 hours from presentation or after serial testing 6 to 12 hours from symptom onset in those presenting earlier (standard care). Sites were paired on the basis of the expected number of patients and randomized to implement the early rule-out pathway (intervention) in 1 of 3 steps during a 6-month randomization phase. All sites completed an implementation phase of at least 6 months that was calendar-matched to the validation phase where patient care was guided by the early rule-out pathway. B, The early rule-out pathway rules out myocardial infarction at presentation in patients with cardiac troponin concentrations below a risk stratification threshold of 5 ng/L, unless they presented within 2 hours of symptom onset when testing was repeated 3 hours from presentation. Patients with cardiac troponin concentrations ≥5 ng/L at presentation are retested in the emergency department 3 hours after presentation and myocardial infarction is ruled out if concentrations are unchanged (Δ <3 ng/L) and remain <99th percentile diagnostic threshold. HiSTORIC indicates High-Sensitivity Cardiac Troponin on Presentation to Rule Out Myocardial Infarction.

Figure 2.

The HiSTORIC trial Consolidated Standards of Reporting Trials diagram. HiSTORIC indicates High-Sensitivity Cardiac Troponin on Presentation to Rule Out Myocardial Infarction; and hs-cTnI, high-sensitivity cardiac troponin I.

Figure 3.

Length of stay before and after implementation of the early rule-out pathway. Shown is a density plot of the length of stay in patients evaluated before (blue) and after (red) implementation of the early rule-out pathway. hs-cTnI indicates high-sensitivity cardiac troponin I; and STEMI, ST-segment–elevation myocardial infarction.

Figure 4.

Myocardial infarction or cardiac death after discharge before and after implementation of the early rule-out pathway. Shown are cumulative incidence time-to-event curves for the primary safety outcome of myocardial infarction or cardiac death for patients evaluated before (blue line) and after (red line) implementation of the early rule-out pathway.